In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group, namely the ionotropic receptors, forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein coupled receptors.
At present, eight different members of these mGluR are known and of these some even have sub-types. According to their sequence homology, signal transduction mechanisms and agonist selectivity, these eight receptors can be sub-divided into three sub-groups: mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer""s disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington""s chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.
Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer""s disease, senile dementia, Parkinson""s disease, Huntington""s chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression and pain. Selective mGluR5 antagonists are especially useful for the treatment of anxiety and pain.
The present invention is a method of treatment of mGluR5 receptor mediated disorders by administering a therapeutically effective amount phenylethenyl and phenylethynyl derivatives of the compound formula 
wherein
R1, R2, R3, R4 and R5, are independently selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)n-halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94NRRxe2x80x2, xe2x80x94(CH2)nxe2x80x94N(R)xe2x80x94C(O)-lower alkyl, aryl or heteroaryl which is unsubstituted or substituted by one or more lower alkyl residues;
R, Rxe2x80x2 and Rxe2x80x3 are independently selected from the group consisting of hydrogen and lower alkyl;
A is selected from the group consisting of xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94; and
B is selected from the group consisting of 
wherein
R6 is selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94C(O)OR and halogen;
R7 is selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94C(O)ORxe2x80x2, halogen, nitro, unsubstituted heteroaryl and heteroaryl substituted by lower alkyl or cycloalkyl;
R8 is selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)nxe2x80x94C(O)ORxe2x80x3 and aryl;
R9 is lower alkyl;
R10 is selected from the group consisting of hydrogen, lower alkyl and halogen;
R11 is selected from the group consisting of hydrogen and alkyl;
R12 is xe2x80x94(CH2)nxe2x80x94N(R)xe2x80x94C(O)-lower alkyl;
R13 selected from the group consisting of hydrogen and lower alkyl;
R14, R15, R16 and R17 are independently selected from the group consisting of, hydrogen, lower alkyl, xe2x80x94(CH2)n-halogen and lower alkoxy;
R18, R19 and R20 are independently selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)n-halogen and lower alkoxy;
R21 is hydrogen or lower alkyl;
R22 is selected from the group consisting of hydrogen, lower alkyl and lower alkyl with at least one substituent selected from the group consisting of hydroxy or halogen;
R23 is selected from the group consisting of hydrogen, lower alkyl, lower alkanoyl and nitro;
R24, R25 and R26, are independently selected from the group consisting of hydrogen and lower alkyl;
n is 0, 1, 2, 3, 4, 5 or 6;
X is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; and
Y is xe2x80x94CHxe2x95x90 or xe2x80x94Nxe2x95x90;
or a pharmaceutically acceptable salt thereof.
Some compounds of the present formula I are known compounds and are described in the literature. For example the synthesis of 1-methyl-2-phenylethynyl-1H-imidazole, 1-methyl-5-phenylethynyl-1H-imidazole and 1-methyl-4-phenylethynyl-1H-imidazole as well as the synthesis of the corresponding phenylethenyl derivatives is described in Chem. Pharm. Bull. 1987, 35(2), 823-828. The compounds have been prepared by palladium catalyzed reaction of corresponding halogen-1,3-azoles with phenylacetylene or styrene. 1-Methyl-2-(4-methoxy-phenylethynyl)-1H-imidazole can be synthesized as nonlinear optical chromophore according to Chem Mater. 1994, 6(7), 1023-1032. The preparation of 2-alkyl-5-phenylethynyl-1H-imidazole-4-carboxaldehydes as intermediates for the manufacture of substituted imidazoles for use as angiotensin II blockers has been described in WO 91/00277. 1-Methyl-5-(2-phenyl-ethenyl)-1H-imidazole has also been prepared as intermediate for the synthesis of heterocyclic food mutagens according to Environ. Health Perspect. 1986, 67, 41-45.
It has now surprisingly been found that compounds of formula I are metabotropic glutamate receptor antagonists having valuable therapeutic properties.
The present invention also relates to novel compounds of the formula 
wherein
R1, R2, R3, R4 and R5 are independently selected from the group consisting of, hydrogen, lower alkyl, xe2x80x94(CH2)n-halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94NRRxe2x80x2, xe2x80x94(CH2)nxe2x80x94N(R)xe2x80x94C(O)-lower alkyl, aryl, unsubstituted heteroaryl and heteroaryl substituted by one or more lower alkyl residues;
R, Rxe2x80x2 and Rxe2x80x3 are selected from the group consisting hydrogen and lower alkyl;
B is selected from the group consisting of 
wherein
R6 is selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94C(O)OR and halogen;
R7 is selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94C(O)ORxe2x80x2, halogen, nitro, unsubstituted heteroaryl and heteroaryl substituted by lower alkyl or cycloalkyl;
R8 is selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)nxe2x80x94C(O)ORxe2x80x3 and aryl;
R9 is lower alkyl;
R10 is selected from the group consisting of hydrogen, lower alkyl and halogen;
R11 is hydrogen or alkyl;
R12 is xe2x80x94(CH2)nxe2x80x94N(R)xe2x80x94C(O)-lower alkyl;
R13 is hydrogen or lower alkyl;
R14, R15, R16 and R17 are independently selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)n-halogen and lower alkoxy;
R18, R19 and R20 are independently selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)n-halogen or lower alkoxy;
R21 signifies hydrogen or lower alkyl;
R22 signifies hydrogen, lower alkyl or lower alkyl carrying at least one substituents selected from hydroxy and halogen;
R23 is selected from the group consisting of hydrogen, lower alkyl, lower alkanoyl and nitro;
R24, R25 and R26 are independently selected from the group consisting of hydrogen and lower alkyl;
n is 0, 1, 2, 3, 4, 5 or 6;
X is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; and
Y is xe2x80x94CHxe2x95x90 or xe2x80x94Nxe2x95x90;
and pharmaceutically acceptable salt thereof; with the exception of
1-methyl-2-phenylethynyl-1H-imidazole,
1-methyl-2-(4-methoxy-phenylethynyl)-1H-imidazole,
1-methyl-5-phenylethynyl-1H-imidazole, and
1-methyl-4-phenylethynyl-1H-imidazole.
Furthermore, the present invention is a compound of the formula 
wherein
R1, R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)n-halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94NRRxe2x80x2, xe2x80x94(CH2)nxe2x80x94N(R)xe2x80x94C(O)-lower alkyl, aryl, unsubstituted heteroaryl and heteroaryl substituted by at least one lower alkylresidues;
R,Rxe2x80x2 and Rxe2x80x3 are hydrogen or lower alkyl;
R6 is selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94C(O)OR and halogen;
R7 is selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94C(O)ORxe2x80x2, halogen, nitro, unsubstituted heteroaryl and heteroaryl substituted by lower alkyl or cycloalkyl; and
R8 signifies hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)nxe2x80x94C(O)ORxe2x80x3 or aryl;
or a pharmaceutically acceptable salt thereof.
The present invention also is a compound of formula 
wherein
R1, R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)n-halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94NRRxe2x80x2,xe2x80x94(CH2)nxe2x80x94N(R)xe2x80x94C(O)-lower alkyl, aryl, unsubstituted heteroaryl and heteroaryl substituted by at least one lower alkyl;
R and Rxe2x80x2 are independently selected from the group consisting of hydrogen and lower alkyl;
R9 is lower alkyl;
R10 is halogen; and
R11 is selected from the group hydrogen or alkyl;
or a pharmaceutically acceptable salt thereof.
The following definitions of general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination. The term xe2x80x9clower alkylxe2x80x9d used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated carbocyclic group containing from 3 to 7 carbon atoms, preferred are cyclopropyl, cyclopentyl or cyclohexyl.
The term xe2x80x9chalogenxe2x80x9d denotes fluorine, chlorine, bromine and iodine.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a lower alkyl group as defined hereinbefore, which is bound via an oxygen atom, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like.
Preferred lower alkanoyl groups are formyl, ethanoyl or propanoyl.
Preferred aryl groups are phenyl or naphthyl.
Heteroaryl groups are selected from furyl, pyrrolyl, thienyl, 1H-imidazolyl, 2H-imidazolyl, 4H-imidazolyl, 1H-pyrazolyl, 3H-pyrazolyl, 4H-pyrazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1H-[1,2,4]triazolyl, 4H-[1,2,4]triazolyl, 1H-[1,2,3]triazolyl, 2H-[1,2,3]triazolyl, 4H-[1,2,3]triazolyl, [1,2,4]oxadiazolyl, [1,3,4]oxadiazolyl, [1,2,3]oxadiazolyl, 1H-tetrazolyl, 2H-tetrazolyl, [1,2,3,4]oxatriazolyl, [1,2,3,5]oxatriazolyl, 1,3-thiazolyl, 1,2-thiazolyl, 1H-pentazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, quinolinyl and their dihydro derivatives. When the heteroaryl group is substituted, it is preferably subsituted by lower alkyl or cycloalkyl. Preferred heteroaryl groups are pyrrolyl and [1,2,4]oxadiazolyl, either substituted or unsubstituted.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to any salt derived from an inorganic or organic acid or base which possesses the desired pharmacological activity of the parent compound.
Especially preferred are compounds of formula I for the above mentioned method of treatment, in which A signifies xe2x80x94Cxe2x89xa1Cxe2x80x94 and B signifies B1.
The following are examples of such compounds:
3,5-dimethyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethyl ester,
5-methyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-(3-methoxy-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
1-methyl-2-phenylethynyl-1H-imidazole,
2-(5-nitro-2-phenylethynyl-imidazol-1-yl)-ethanol,
2-phenylethynyl-1H-imidazole,
2-(2,6-dichloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
5-methyl-1-phenyl-2-phenylethynyl-1 H-imidazole-4-carboxylic acid ethyl ester,
3,5-dimethyl-2-m-tolylethynyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-(3-acetylamino-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-[3-(2,5-dimethyl-pyrrol-1-yl)-phenylethynyl]-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
5-(3,5-dimethyl-2-phenylethynyl-3H-imidazol-4-yl)-3-methyl-[1,2,4]oxadiazole,
3-cyclopropyl-5-(3,5-dimethyl-2-phenylethynyl-3H-imidazol-4-yl)-[1,2,4]oxadiazole,
2-(4-chloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-(4-fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-biphenyl-4-ylethynyl-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-(2-fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-(2-fluoro-phenylethynyl)-1-methyl-1H-imidazole,
2-(4-amino-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-(2-chloro-phenylethynyl)-1-methyl-1H-imidazole and
(4,5-dichloro-2-phenylethynyl-imidazol-1-yl)-acetic acid ethyl ester.
Further preferred are compounds of formula I for the above mentioned method of treatment, in which A signifies xe2x80x94Cxe2x89xa1Cxe2x80x94 and B signifies B2.
An example for such a compound is 1-methyl-5-phenylethynyl-1H-imidazole.
Also preferred for the above mentioned method of treatment are compounds of formula I, in which A signifies xe2x80x94Cxe2x89xa1Cxe2x80x94 and B signifies B3.
An example for such a compound is N-[2-(5-methoxy-2-phenylethynyl-1H-indol-3-yl)-ethyl]-acetamide.
Preferred compounds of formula I for the above mentioned method of treatment are also those, in which A signifies xe2x80x94Cxe2x89xa1Cxe2x80x94 and B signifies B4.
The following are examples of such compounds:
3-phenylethynyl-4H-5-thia-2,6,9b-triaza-cyclopenta[a]naphthalene or
3-phenylethynyl-4H-5-oxa-2,9b-diaza-cyclopenta[a]naphthalene.
Further preferred are compounds of formula I for the above mentioned method of treatment, in which A signifies xe2x80x94Cxe2x89xa1Cxe2x80x94 and B signifies B5.
Examples of such compounds are:
1-chloro-3-(2-methyl-5-nitro-4-phenylethynyl-imidazol-1-yl)-propan-2-ol,
3-methyl-5-phenylethynyl-3H-imidazole-4-carbaldehyde,
4-phenylethynyl-1H-imidazole,
1-methyl-4-phenylethynyl-1H-imidazole and
1,2-dimethyl-5-nitro-4-phenylethynyl-1H-imidazole.
Also preferred are compounds of formula I for the above mentioned method of treatment in which A signifies xe2x80x94Cxe2x89xa1Cxe2x80x94 and B signifies B6.
An example for such a compound is 1,3-dimethyl-5-phenylethynyl-1H-pyrazole.
Further preferred are compounds of formula I for the above mentioned method of treatment, in which A signifies xe2x80x94Cxe2x95x90Cxe2x80x94.
Especially preferred are those compounds of formula I for the above mentioned method of treatment, in which A signifies xe2x80x94Cxe2x95x90Cxe2x80x94 and B signifies B1.
The following are examples of such compounds:
4,5-diisopropyl-1-methyl-2-styryl-1H-imidazole,
2-[2-(4-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,
2-[2-(4-chloro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,
2-[2-(4-butoxy-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,
4,5-diisopropyl-2-[2-(4-methoxy-2,3,6-trimethyl-phenyl)-vinyl]-1-methyl-1H-imidazole,
4,5-diisopropyl-2-[2-(4-methoxy-phenyl)-vinyl]-1-methyl-1H-imidazole,
2-[2-(4-chloro-3-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,
2-[2-(4-ethoxy-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,
4,5-diisopropyl-1-methyl-2-[2-(2,3,4-trimethoxy-phenyl)-vinyl]-1H-imidazole,
2-[2-(2,4-dichloro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole and
4,5-diisopropyl-1-methyl-2-(2-p-tolyl-vinyl)-1H-imidazole.
Also preferred are compounds of formula I for the above mentioned method of treatment, in which A signifies xe2x80x94Cxe2x95x90Cxe2x80x94 and B signifies B2.
Examples of such compounds are the following:
4-bromo-1-methyl-5-styryl-1H-imidazole and
1-methyl-5-styryl-1H-imidazole.
Further preferred objects of the present invention are compounds of formula I-A, in which B signifies B1 with the exception of 1-methyl-2-phenylethynyl-1H-imidazole and 1-methyl-2-(4-methoxy-phenylethynyl)-1H-imidazole.
The following are examples of such compounds:
2-(5-nitro-2-phenylethynyl-imidazol-1-yl)-ethanol,
2-phenylethynyl-1H-imidazole,
2-(2-fluoro-phenylethynyl)-1-methyl-1H-imidazole,
2-(2-chloro-phenylethynyl)-1-methyl-1H-imidazole and
(4,5-dichloro-2-phenylethynyl-imidazol-1-yl)-acetic acid ethyl ester.
More preferred are compounds of formula I-A, in which B signifies B1 and R7 is selected from the group consisting of (CH2)nxe2x80x94C(O)ORxe2x80x2, unsubstituted heteroaryl and heteroaryl substituted by lower alkyl or cycloalkyl.
Especially preferred are those, in which R7 signifies (CH2)nxe2x80x94C(O)ORxe2x80x2, wherein n is 0 and R is lower alkyl.
Examples of such compounds are the following:
3,5-dimethyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethyl ester,
5-methyl-2-phenylethynyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-(3-methoxy-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-(2,6-dichloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
5-methyl-1-phenyl-2-phenylethynyl-1H-imidazole-4-carboxylic acid ethyl ester,
3,5-dimethyl-2-m-tolylethynyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-(3-acetylamino-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-[3-(2,5-dimethyl-pyrrol-1-yl)-phenylethynyl]-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
5-(3,5-dimethyl-2-phenylethynyl-3H-imidazol-4-yl)-3-methyl-[1,2,4]oxadiazole,
3-cyclopropyl-5-(3,5-dimethyl-2-phenylethynyl-3H-imidazol-4-yl)-[1,2,4]oxadiazole,
2-(4-chloro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-(4-fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-biphenyl-4-ylethynyl-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester,
2-(2-fluoro-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester, and
2-(4-amino-phenylethynyl)-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.
Also preferred are compounds of formula I-A, in which B signifies B4.
The following are examples of such compounds:
3-phenylethynyl-4H-5-thia-2,6,9b-triaza-cyclopenta[a]naphthalene and
3-phenylethynyl-4H-5-oxa-2,9b-diaza-cyclopenta[a]naphthalene.
Preferred compounds of formula I-A are also those, in which B signifies B5 with the exception of 1-methyl-4-phenylethynyl-1H-imidazole.
Examples of such compounds are the following:
1-chloro-3-(2-methyl-5-nitro-4-phenylethynyl-imidazol-1-yl)-propan-2-ol,
3-methyl-5-phenylethynyl-3H-imidazole-4-carbaldehyde,
4-phenylethynyl-1H-imidazole and
1,2-dimethyl-5-nitro-4-phenylethynyl-1H-imidazole.
Also preferred is a compound of formula 
wherein
R1, R2, R3, R4 and R5 are independently selected from the group consisting of each other, hydrogen, lower alkyl, xe2x80x94(CH2)n-halogen, lower alkoxy, xe2x80x94(CH2)nxe2x80x94NRRxe2x80x2, xe2x80x94(CH2)nxe2x80x94N(R)xe2x80x94C(O)-lower alkyl, aryl, unsubstituted heteroaryl and heteroaryl substituted by at least one lower alkyl; and in which B signifies B1 and R7 signifies lower alkyl or xe2x80x94(CH2)nxe2x80x94C(O)ORxe2x80x2.
Especially preferred are those in which R7 is lower alkyl.
Examples of such compounds are the following:
4,5-diisopropyl-1-methyl-2-styryl-1H-imidazole,
2-[2-(4-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,
2-[2-(4-chloro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,
2-[2-(4-butoxy-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,
4,5-diisopropyl-2-[2-(4-methoxy-2,3,6-trimethyl-phenyl)-vinyl]-1-methyl-1H-imidazole,
4,5-diisopropyl-2-[2-(4-methoxy-phenyl)-vinyl]-1-methyl-1H-imidazole,
2-[2-(4-chloro-3-fluoro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,
2-[2-(4-ethoxy-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole,
4,5-diisopropyl-1-methyl-2-[2-(2,3,4-trimethoxy-phenyl)-vinyl]-1H-imidazole,
2-[2-(2,4-dichloro-phenyl)-vinyl]-4,5-diisopropyl-1-methyl-1H-imidazole and
4,5-diisopropyl-1-methyl-2-(2-p-tolyl-vinyl)-1H-imidazole.
Further preferred compounds of formula I-B are those, in which B signifies B2 and R10 is halogen.
An example of such a compound is 4-bromo-1-methyl-5-styryl-1H-imidazole.
The present compounds of formula I-A and I-B and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises reacting a compound of the formula 
with a compound of formula
Bxe2x80x94Xxe2x80x83xe2x80x83III
wherein
X signifies halogen or trifluoromethanesulfonyl and
R1 to R5 have the significances as defined before,
to obtain a compound of formula I-A in the case if A signifies xe2x80x94Cxe2x89xa1Cxe2x80x94 and B has the significances as defined before;
or to obtain a compound of formula I-B in the case if A signifies xe2x80x94HCxe2x95x90CHxe2x80x94 and B is 
wherein
R6 is selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94C(O)OR and halogen;
R7 is selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94C(O)ORxe2x80x2, halogen, nitro, or unsubstituted heteroaryl and heteroaryl substituted by lower alkyl or cycloalkyl;
R8 is selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)nxe2x80x94C(O)ORxe2x80x3 and aryl;
R9 is lower alkyl;
R10 is halogen; and
R11 is selected from the group hydrogen and alkyl;
and if desired, converting a compound of formulas I-A or I-B into a pharmaceutically acceptable salt.
This process is catalyzed by palladium(II) salts.
In accordance with the invention, compounds of formula I, wherein A signifies xe2x80x94Cxe2x89xa1Cxe2x80x94, are prepared by reacting an acetylene derivative of formula II, for example ethynylbenzene, with a suitable compound of formula III, for example 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ester. According to the method as described in Chem. Pharm. Bull. 1987, 35(2), 823-828 this palladium catalyzed Cxe2x80x94C-coupling reaction requires the presence of bis(triphenylphosphine)-palladium(II)-chloride, cuprous iodide and triethylamine and is carried out in a polar solvent like dimethylformamide or acetonitrile at a temperature of 90xc2x0 C. to 100xc2x0 C. within 1.5 to 3 hours. The reaction can also be carried out in the presence equimolar amounts of bis(triphenylphosphine)-palladium(II)-chloride and triphenylphosphine and an excess of triethylamine at a temperature of 55xc2x0 C. within 16 hours.
The phenylethynyl derivatives of formula II are commercially available or can be easily prepared by methods well known in the art.
The compounds of formula III are also commercially available or can be prepared by appropiate methods depending on the heterocyclic system B.
2-Halogeno-1H-imidazoles of formula III (B=B1) are prepared according to methods as described in U.S. Pat. Nos. 4,711,962, 3,341,548 and Synth. Commun. 1989, 19, 2551-2566.
2-Trifluoromethanesulfonyl-1H-imidazoles of formula IIIa can be prepared from a 2-oxo-2,3-dihydro-1H-imidazole of formula VI, for example from 5-methyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic acid ethyl ester which is obtained according to the method as described in U.S. Pat. No. 3,303,199. The reaction with trifluoromethanesulfonic anhydride and triethylamine is carried out in dichloromethane at room temperature (Scheme 1, Tf=trifluoromethanesulfonyl). 
5-(2-Bromo-3,5-dimethyl-3H-imidazol-4-yl)-[1,2,4]oxadiazoles of formula IIIb are obtained by reacting 3,5-dimethyl-3H-imidazole-4-carboxylic acid VII with N-hydroxy-carboxamidines of formula VIII in the presence of 1,1xe2x80x2-carbonyldiimidazole and dimethyl-formamide as solvent to give imidazolyl-[1,2,4]oxadiazoles of formula IX which are then brominated at room temperature (Scheme 2, Rxe2x80x3 is lower alkyl or cycloalkyl). 
A suitable indole derivative of formula III (B=B3), for example N-[2-(2-iodo-5-methoxy-1H-indol-3-yl)-ethyl]-acetamide, can be obtained in accordance with the method as described in J. Labelled Compd. Radiopharm. 1997, 39, 677-684.
3-Iodo-4H-5-thia-2,6,9b-triaza-cyclopenta[a]naphthalenes and 3-iodo-4H-5-oxa-2,9b-diaza-cyclopenta[a]naphthalenes of formula III (B=B4) are prepared in analogy to the method as described in EP 0 059 390.
4-Halogeno-1H-imidazoles of formula III (B=B5) can be obtained according to methods as described for example in J. Med. Chem. 1974, 17(9), 1019-1020, Chem. Pharm. Bull. 1994, 42, 1784-1790 or Aust. J. Chem. 1987, 40(8), 1399-1413.
Compounds of formula III, in which B signifies B6, can be prepared for example in analogy to a method described in Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.) 1983, 626-628 and in Izv. Akad. Nauk SSSR Ser. Khim. 1983, 688-690.
Phenylethenyl derivatives of formula I can be prepared analogously by reacting a compound of formula III with a phenylethene of formula II.
Furthermore, compounds of formula I, in which A signifies xe2x80x94Cxe2x95x90Cxe2x80x94, and their pharmaceutically acceptable salts can also be obtained by reacting a compound of the formula 
wherein
X1 is halogen,
with a compound of the formula 
to obtain a compound of formula 
wherein
R1 to R5 are as described above and B is 
wherein
R6 is selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94C(O)OR and halogen;
R7 is selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94C(O)ORxe2x80x2, halogen, nitro, unsubstituted heteroaryl unsubstituted and heteroaryl substituted by lower alkyl or cycloalkyl;
R8 is selected from the group consisting of hydrogen, lower alkyl, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)nxe2x80x94C(O)ORxe2x80x3 and aryl;
R9 is lower alkyl;
R10 is halogen; and
R11 is selected from the group consisting of hydrogen or alkyl;
and converting a compound of formula I-B into a pharmaceutically acceptable salt.
Thus, compounds of formula I-B are obtained in a Wittig reaction by treating an appropiate aldehyde of formula V, for example 4,5-diisopropyl-1-methyl-1H-imidazole-2-carbaldehyde, with a suitable benzyltriphenylphosphonium halide of formula IV, for example benzyltriphenylphosphoniumchloride in the presence of a strong base like a sodium alkoxide, sodium amide or sodium hydride.
Triphenylphosphonium salts of formula IV are prepared from triphenylphosphine (PPh3) and the appropiate benzyl halides X (Scheme 3). 
Aldehydes of formula V can be obtained by methods known in the art. For example, 4,5-diisopropyl-1-methyl-1H-imidazole-2-carbaldehyde is prepared in analogy with a method as described in Inorg. Chim. Acta 1999, 296 (1), 208-221, and 5-bromo-3-methyl-3H-imidazole-4-carbaldehyde is obtained in accordance to a method as described in Chem. Pharm. Bull. 1994, 42, 1784-1790.
The pharmaceutically acceptable salts of compounds of formula I-A and I-B can be manufactured readily according to methods known to those skilled in the art taking, into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids are suitable for the formation of pharmaceutically acceptable salts of acidic compounds.
The compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, metabotropic glutamate receptor antagonists and can be used for the treatment or prevention of mGluR5 receptor mediated disorders, such as acute and/or chronic neurological disorders, cognitive disorders and memory deficits, as well as acute and chronic pain. Treatable neurological disorders are for instance epilepsy, schizophrenia, anxiety, acute, traumatic or chronic degenerative processes of the nervous system, such as Alzheimer""s disease, senile dementia, Huntington""s chorea, ALS, multiple sclerosis, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression. Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia.
The compounds of formula I and their pharmaceutically acceptable salts are especially useful as analgesics. Treatable kinds of pain include inflammatory pain such as arthritis and rheumatoid disease, vasculitis, neuropathic pain such as trigeminal or herpetic neuralgia, diabetic neuropathy pain, causalgia, hyperalgesia, severe chronic pain, post-operative pain and pain associated with various conditions like cancer, angina, renal or billiay colic, menstruation, migraine and gout.
The pharmacological activity of all of the example compounds was tested using the following method:
cDNA encoding rat mGlu 5a receptor was transiently transfected into EBNA cells using a procedure described by E.-J. Schlaeger and K. Christensen (Transient gene expression in mammalian cells grown in serum-free suspension culture; Cytotechnology, 30: 71-83,1999). [Ca2+]i measurements were performed on mGlu 5a transfected EBNA cells after incubation of the cells with Fluo 3-AM (obtainable by FLUKA, 0.5 xcexcM final concentration) for 1 hour at 37xc2x0 C. followed by 4 washes with assay buffer (DMEM supplemented with Hank""s salt and 20 mM HEPES. [Ca2+]i measurements were done using a fluorometric imaging plate reader (FLIPR, Molecular Devices Corporation, La Jolla, Calif., USA). When compounds were evaluated as antagonists they were tested against 10 xcexcM glutamate as agonist.
The inhibition (antagonists) curves were fitted with a four parameter logistic equation giving IC50, and Hill coefficient using the iterative non linear curve fitting software Origin (Microcal Software Inc., Northampton, Mass., USA).
The compounds of the present invention are mGluR 5a receptor antagonists. The compounds show activities, as measured in the assay described above, of 10 xcexcM or less, typically 2 xcexcM or less, and preferably of 0.02 xcexcM or less.
In the Table I below are shown specific activity data of the compounds of the present invention derived according to the procedure described above:
The compounds of formula I and pharmaceutically acceptable salts thereof can be used as pharmaceutical compositions, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical compositions. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragxc3xa9es and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical compositions can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
As mentioned earlier, pharmaceutical compositions containing a therapeutically effective amount of compound of formula IA or IB or pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such pharmaceutical compositions which comprises bringing one or more compounds of formula IA or IB or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and will, of course, be adapted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
Finally, as mentioned earlier, the use of compounds of formula I and of pharmaceutically acceptable salts thereof for the production of pharmaceutical compositions, especially for the for the treatment or prevention of mGluR5 receptor mediated disorders of the aforementioned kind, is also an object of the invention.
The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.